Indole diterpenoid synthetic studies. The total synthesis of (+)-nodulisporic acid F

Article abstract of DOI:10.1021/ol060290+

A stereocontrolled total synthesis of (+)-nodulisporic acid F, the simplest member of a family of novel ectoparasiticidal agents, has been achieved. Highlights of the effective modular synthetic strategy include anionic union of a tricyclic lactone with o

Full text of DOI:10.1021/ol060290+

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1665-1668
Indole Diterpenoid Synthetic Studies.
The Total Synthesis of (
Acid F
+
)-Nodulisporic
Amos B. Smith, III,* Akin H. Davulcu, and La´szlo´ Ku
1
rti
Department of Chemistry, Monell Chemical Senses Center and Laboratory for
Research on the Structure of Matter, UniVersity of PennsylVania,
Philadelphia, PennsylVania 19104
smithab@sas.upenn.edu
Received February 2, 2006
ABSTRACT
A stereocontrolled total synthesis of (
achieved. Highlights of the effective modular synthetic strategy include anionic union of a tricyclic lactone with o-toluidine via our 2-substituted
indole synthetic protocol, an optimized C-ring construction protocol, and a late-stage installation of the -unsaturated carboxylic acid side
chain via the B-alkyl Suzuki Miyaura cross-coupling tactic.
+)-nodulisporic acid F, the simplest member of a family of novel ectoparasiticidal agents, has been
r,â
−
(+)-Nodulisporic acid A (1; Figure 1), an indole diterpenoid
reported by Ondeyka and co-workers in 1997,1 produced by
the endophytic fungus, Nodulisporium sp. (MF5954), was
reported to be an effective systemic ectoparasiticidal agent
against fleas on dogs. The mode of action emanates from
modulation of invertebrate-specific glutamate-gated chloride
ion channels;2 thus nodulisporic acid A (1) is devoid of
mammalian toxicity. Although exhibiting good in vitro and
in vivo activity against fleas, the potency and pharmacoki-
netic profile did not justify direct commercialization. A
medicinal chemistry campaign was therefore undertaken by
Merck and Co. to optimize the profile of this lead compound.
Synthetic efforts focusing on the dienoic acid side chain of
the molecule culminated in the synthesis of over 1000
analogues.3 In parallel with medicinal chemistry efforts,
Merck scientists sought congeners and/or natural analogues
of the parent compound, both from the original producer as
well as variants derived by chemical mutagenesis. The latter
effort led to the discovery of nodulisporic acids A1, A2, B,
B1, B2, C, C1, C2, as well as putative biosynthetic intermedi-
ates nodulisporic acids D (2), D1, D2, D3, E, and F (3; Figure
1).4
Given our long-standing interest in the indole-diterpenoid
class of natural products,5 the nodulisporic acids captured
our attention as worthy synthetic targets. From the outset,
our ultimate goal was to devise a convergent, modular
synthetic strategy that would permit access to all of the
nodulisporic acids, as well as to an array of unnatural
(1) (a) Ondeyka, J. G.; Helms, G. L.; Hensens, O. D.; Goetz, M. A.;
Zink, D. L.; Tsipouras, A.; Shoop, W. L.; Slayton, L.; Dombrowski, A.
W.; Polishook, J. D.; Ostlind, D. A.; Tsou, N. N.; Ball, R. G.; Singh, S. B.
J. Am. Chem. Soc. 1997, 119, 8809. (b) Ostlind, D. A.; Felcetto, T.; Misura,
A.; Ondeyka, J. G.; Smith, S.; Goetz, M.; Shoop, W.; Mickle, W. Med.
Vet. Entomol. 1997, 11, 407.
(2) Ludmerer, S. W.; Warren, V. A.; Williams, B. S.; Zheng, Y. C.;
Hunt, D. C.; Ayer, M. B.; Wallace, M. A.; Chaudhary, A. G.; Egan, M. A.;
Meinke, P. T.; Dean, D. C.; Garcia, M. L.; Cully, D. F.; Smith, M. M.
Biochemistry 2002, 41, 6548 and references therein.
(3) Chakravarty, P. K.; Shih, T. L.; Colletti, S. L.; Ayer, M. B.; Snedden,
C.; Kuo, H.; Tyagarajan, S.; Gregory, L.; Zakson-Aiken, M.; Shoop, W.
L.; Schmatz, D. M.; Wyvratt, M. J.; Fisher, M. H.; Meinke, P. T. Bioorg.
Med. Chem. Lett. 2003, 13, 147 and references therein.
(4) Singh, S. B.; Ondeyka, J. G.; Jayasuriya, H.; Zink, D. L.; Ha, S. N.;
Dahl-Roshak, A. M.; Greene, J.; Kim, J. A.; Smith, M. M.; Shoop, W.;
Tkacz, J. S. J. Nat. Prod. 2004, 67, 1496 and references therein.
10.1021/ol060290+ CCC: $33.50
© 2006 American Chemical Society
Published on Web 03/24/2006

N-silylated dianion derived from o-toluidine (7) with known
tricyclic lactone (+)-8.9
In the event, treatment of the N-silylated dianion derived
in situ from N-trimethylsilyl-o-toluidine with lactone (+)-8
furnished ketoaniline (+)-9 in near quantitative yield (Scheme
2). The failure to undergo the expected indolization, known
Scheme 2. Access to the Pentacyclic Core of 3
Figure 1. Representative nodulisporic acid congeners.
analogues not easily accessible by chemical modification of
the naturally occurring indoles. The cornerstone of the
proposed synthetic strategy would entail the 2-substituted
indole synthesis that we introduced in 1986 and have
subsequently developed.6 To initiate this program, we
selected (+)-nodulisporic acid F (3), the simplest congener
of the nodulisporane family, as our initial target.
From the synthetic perspective, we envisioned that (+)-
nodulisporic acid F could be assembled via a late-stage
B-alkyl Suzuki-Miyaura cross-coupling7 of pentacyclic
indole 4 with methyl-(E)-3-bromo-2-methylpropenoate
(Scheme 1). Indole 4 in turn was expected to arise via
to occur in simpler systems, is attributed to steric effects
exerted by the adjacent C3 (nodulisporic acid numbering)
quaternary center, which is thought to attenuate the rate of
the requisite heteroatom-Peterson olefination relative to the
thermodynamically driven intramolecular N f O silyl
migration. Pleasingly, acid-catalyzed cyclodehydration fur-
nished indole (+)-6 in 95% yield, which was then readily
converted to the corresponding mesylate (+)-10 (e.g., MsCl,
DMAP; 98% yield). Turning to construction of ring C, we
planned to take advantage of a previous observation in our
laboratory8 which demonstrated that indoles similar to (+)-
10 would undergo cyclization in a regioselective manner at
the C3 indole position via the corresponding indolyl N-
Grignard species, despite the inherent stereoelectronic bias
favoring reaction at N1, simply by executing the reaction at
elevated temperatures. Implementation of these conditions
yielded a mixture (2.5:1.0) of regioisomers (+)-5 and (+)-
Scheme 1. First-Generation Retrosynthetic Analysis
(5) (a) Smith, A. B., III; Mewshaw, R. E. J. Am. Chem. Soc. 1985, 107,
1796. (b) Mewshaw, R. E.; Taylor, M. D.; Smith, A. B., III. J. Org. Chem.
1989, 54, 3449. (c) Smith, A. B., III; Sunazuka, T.; Leenay, T. L.; Kingery-
Wood, J. J. Am. Chem. Soc. 1990, 112, 8197. (d) Smith, A. B., III; Kanoh,
N.; Minakawa, N.; Rainier, J. D.; Blase, F. R.; Hartz, R. A. Org. Lett. 1999,
1, 1263. (e) Smith, A. B., III; Kanoh, N.; Ishiyama, H.; Hartz, R. A. J. Am.
Chem. Soc. 2000, 114, 1438. (f) Smith, A. B., III; Naoki, K.; Ishiyama, H.;
Minikawa, N.; Rainier, J. D.; Hartz, R. A.; Cho, Y. S.; Cui, H.; Moser, W.
H. J. Am. Chem. Soc. 2003, 125, 8228.
(6) Smith, A. B., III; Visnick, M.; Haseltine, J. N.; Sprengler, P. A.
Tetrahedron 1986, 42, 2957.
(7) Miyaura, N.; Ishiyama, T.; Sasaki, H.; Ishikawa, M.; Satoh, M.;
Suzuki, A. J. Am. Chem. Soc. 1989, 111, 314.
selective removal of the primary TBS group in 5, followed
by oxidation and methylenation. Construction of ring C in 5
would then call for a regioselective intramolecular alkylation
of 6, wherein the alcohol functional group would first be
transformed into a suitable leaving group. This tactic had
been developed in conjunction with our 21-isopentenylpax-
illine8 synthesis. Finally, 6 would arise via union of the
(8) Smith, A. B., III; Cui, H. Org. Lett. 2003, 5, 587.
(9) Smith, A. B., III; Cho, Y. S.; Ishiyama, H. Org. Lett. 2001, 3, 3971.
1666
Org. Lett., Vol. 8, No. 8, 2006

11, respectively, in a combined yield of 48%. The structure
of (+)-11 was verified by X-ray crystallography (Figure 2).
N-zinc species.11 Despite these favorable results, further
advancement of pentacyclic indole (+)-5 toward (+)-
nodulisporic acid F was thwarted by our inability to effect
selective removal of the primary TBS group in the presence
of the C7 secondary TBS ether. Although frustrating, this
result was not entirely unexpected given the neopentyl nature
of the targeted primary TBS ether. From the perspective of
the ultimate goal of defining a modular synthetic strategy,
that might be generally applicable to other members of the
class of nodulisporanes and analogues thereof, this result had
important implications on the design of an endgame se-
quence.
A revised strategy was therefore put forth (Scheme 3),
wherein the originally planned late-stage modifications of
the eastern portion of lactone (+)-8 (Scheme 1) would be
executed prior to union. The requisite lactone (-)-12 was
prepared via a four-step sequence from (+)-8 (Scheme 4)
Figure 2. ORTEP representation of (+)-11.
Efforts to obtain suitable crystals of (+)-5 were unfortunately
complicated by decomposition, presumably via oxidative
cleavage of the indole C2-C14 bond, a now well-known
oxidation process of the indole diterpenes.10
Scheme 3. A Second-Generation Synthetic Strategy
Given the modest regioselectivity in the C-ring construc-
tion, a detailed optimization study was undertaken (Table
1). Best results were obtained when Zn(OTf)2 was added to
Table 1. Optimization of C-Ring Closure
comprising a fluoride-induced desilylation, followed by
selective oxidation of the resulting primary alcohol with
TEMPO/NaOCl under biphasic conditions12 to yield the
corresponding hydroxyaldehyde. Protection of the C7 hy-
droxyl group as the TES ether and Wittig methylenation
furnished (-)-12; the overall yield was 83%.
Scheme 4. Preparation of Lactone (-)-12
conditions
t-BuMgCl, PhMe, 23 °C
ratio 5:11 yield
1.0:8.2
t-BuMgCl, PhMe, 110 °C
Bu2Mg, PhMe, 110 °C
Mg(HMDS)2, PhMe, 110 °C
MeMgI, PhMe, 110 °C
t-BuMgCl, PhMe, Zn(OTf)2 (5 equiv), 110 °C
t-BuMgCl, PhMe, Zn(OTf)2 (10 equiv), 110 °C
2.5:1.0
2.8:1.0
1.0:1.8
7.7:1.0
6.3:1.0
9.0:1.0
48%
42%
21%
41%
63%
72%
As expected, lactone (-)-12 served as a competent
coupling partner when exposed to the N-silylated dianion
derived in situ from N-trimethylsilyl-o-toluidine; the resultant
ketoaniline (85% yield) was then subjected to acid-promoted
cyclodehydration to provide indole (+)-13 in 81% overall
yield for the two steps (Scheme 5). Conversion to the
corresponding mesylate (-)-14 (95% yield), followed by
application of our now optimized conditions for construction
of ring C, returned pentacyclic indole (+)-15 in 59% yield,
accompanied by the N1 regioisomer in ca. 8% yield.
the reaction mixture. For example, treatment of (+)-10 with
t-BuMgCl and Zn(OTf)2 (10 equiv) in PhMe at 110 °C
furnished (+)-5 in 72% isolated yield, accompanied only by
a minor amount of (+)-11 (ca. 7%). Presumably, this reaction
proceeds via in situ transmetalation of the initially formed
indolyl N-Grignard to the more highly covalent indolyl
(10) Sings, H.; Singh, S. In The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Elsevier Academic Press: New York, 2003; Vol. 60,
p 51.
(11) Bergman, J.; Venamalm, L. Tetrahedron 1990, 46, 6061.
(12) de Nooy, A. E. J.; Basemer, A. C.; van Bekkum, H. Synthesis 1996,
1153.
Org. Lett., Vol. 8, No. 8, 2006
1667

Having now achieved construction of the carbon frame-
work of nodulisporic acid F, saponification of methyl ester
(+)-17 to reveal the alkenoic acid side chain (87% yield)
and solvolytic removal of the TES protecting group com-
pleted construction of (+)-nodulisporic acid F (92% yield),
identical in all respects [e.g., 500 MHz 1H NMR, 125 MHz
13C NMR, λmax, HRMS, optical rotation, and TLC (three
solvent systems)] to that of natural (+)-nodulisporic acid F
[(+)-3].
Scheme 5. Total Synthesis of (+)-Nodulisporic Acid F
In summary, the first total synthesis of a member of the
nodulisporic acid family of ectoparasiticidal agents has been
achieved. Highlights of the effective synthetic strategy
include implementation of our 2-substituted indole synthesis,
optimization of the regioselective cyclizations of mesylates
(+)-10 and (-)-14 to effect installation of ring C thereby
securing the pentacyclic core, and application of the B-alkyl
Suzuki-Miyaura cross-coupling reaction to elaborate the
requisite alkenoic acid side chain. Importantly, the modularity
of this strategy holds promise for application to other
members of the nodulisporic acid family. Work toward this
end continues in our laboratory.
Acknowledgment. Financial support was provided by the
National Institutes of Health (National Institute of General
Medical Sciences) through Grant GM-29028 and by the
Bristol-Myers Squibb Pharmaceutical Research Institute
(stipend support of A.H.D.). We also thank Dr. G. Furst,
Dr. R. K. Kohli, and Dr. P. Carroll for assistance in obtaining
NMR spectra, high-resolution mass spectra, and X-ray
crystallographic data, respectively. Finally, we are particu-
larly thankful to Dr. P. T. Meinke and the Merck Research
Laboratories for providing generous financial support of this
research program, and for a sample of natural (+)-no-
dulisporic acid F.
At this juncture, all that remained to complete the synthesis
of (+)-nodulisporic acid F was elaboration of the acid side
chain via the proposed Suzuki-Miyaura cross-coupling.
Despite initial difficulties to transform (+)-15 to the corre-
sponding 9-BBN alkylborane, presumably due to the steri-
cally encumbered nature of the olefin, efficient conversion
was eventually achieved exploiting the crystalline 9-BBN
dimer in toluene at 80 °C, a protocol introduced by Johnson.13
Subsequent solvent exchange to DMF, followed by exposure
to methyl-(E)-3-bromo-2-methylpropenoate (16)14 employing
the Suzuki-Miyaura coupling conditions, furnished (+)-17
in 69% yield.
Supporting Information Available: Spectroscopic and
analytical data for all new compounds, as well as selected
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL060290+
(14) The acid was prepared according to Dzierba, C. D.; Zandi, K. S.;
Mollers, T.; Shea, K. J. J. Am. Chem. Soc. 1996, 118, 4711.
(13) Sabat, M.; Johnson, C. Org. Lett. 2000, 2, 1089.
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Org. Lett., Vol. 8, No. 8, 2006